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The dual function provided by longitudinal tracheids in conifers has led to a generally held trade-off concept that increasing wall thickness and/or volume of latewood tracheids improves mechanical support, while increasing cell diameter and/or volume of earlywood tracheids enhances conductive potential. Yet, some conifers have either uniform cell structure across the growth ring or, at most, a small amount of latewood. How do these trees accomplish the needs for increasing support and conduction with height growth? We examined Metasequoia glyptostroboides, a species that we previously demonstrated improves its mechanical properties with increasing age without a change in specific gravity or secondary wall microfibril angle. In this paper, we showed that lignin and extractive contents are not contributing factors, and through composite structure analysis, we eliminated a role for tracheid length. Using micromorphometric analysis, we demonstrated that as cell diameter increases, total primary wall decreases, secondary wall increases, and strength and conductive capacity increase with no change in specific gravity. Meta-analysis using other species of Cupressaceae, Podocarpaceae, and Araucariaceae provided strong corroborative evidence for this design strategy.

The xylem of Metasequoia glyptostroboides Hu et Cheng is characterized by very low density (average specific gravity = 0.27) and tracheids with relatively large dimensions (length and diameter). The microfibril angle in the S2 layer of tracheid walls is large, even in outer rings, suggesting a cambial response to compressive rather than tensile stresses. In some cases, this compressive stress is converted to irreversible strain (plastic deformation), as evidenced by cell wall corrugations. The heartwood is moderately decay resistant, helping to prevent Brazier buckling. These xylem properties are referenced to the measured bending properties of modulus of rupture and modulus of elasticity, and compared with other low-to-moderate density conifers. The design strategy for Metasequoia is to produce a mechanically weak but hydraulically efficient xylem that permits rapid height growth and crown development to capture and dominate a wet site environment. The adaptability of these features to a high-latitude Eocene palaeoenvironment is discussed.

34-250 evoked hypocholesterolemic activity in the rat (14, 25, 31, 52, 112 mg/kg, po), dog (10, 20, 40 mg/kg, po), and monkey (30 mg/kg, po). Serum triglycerides were lowered in the rat and dog but not in the monkey. 34-250 increased [14C]acetate incorporation into liver cholesterol, but incorporation of 14C-labeled acetate into serum cholesterol was decreased. Desmosterol or 7-dehydro-cholesterol did not accumulate in serum of the three species, suggesting that inhibition of cholesterol biosynthesis by 34-250 possibly does not occur at a late stage. Normal fecal bile acid excretion was observed in rats, suggesting that cholesterol catabolism probably was not enhanced by 34-250. Compound 34-250-induced hypocholesterolemia may result from inhibition of hepatic release of this sterol into blood. The reversible hepatic lipidosis observed in rats is also possibly related to decreased hepatic transport and/or secretion of triglycerides. 34-250 did not cause a proliferation of hepatic microbodies; the lack of an increase in this fatty acid oxidizing organelle suggests that it may also have had a role in increased hepatic lipidosis. In dogs, a high incidence of severe cataracts with an early onset was induced by 20 and 40 mg/kg, po of 34-250 despite the lack of desmosterol or 7-dehydro-cholesterol in serum. The absence of these late stage intermediates of cholesterol biosynthesis in the serum of a test species does not preclude the occurrence of ocular toxicity.

Bodies similar to acidophilic intracytoplasmic inclusions were found by light microscopy in the pancreatic acinar cells of 56 of 174 (32%) healthy male and female purebred Beagles and 14 of 97 (14%) of healthy male mongrel dogs. The inclusions were ovoid, acidophilic and often granular with basophilic particulates. Many seemed to be enclosed within halos of various widths. Electron microscopically the inclusions consisted of whorls of rough endoplasmic reticulum, vacuoles, and cytoplasmic organelles in various stages of decomposition. These inclusion bodies were interpreted as evidence of focal intracytoplasmic degradation. They appeared similar to the dense ribosomal autophagic vacuoles, hitherto described only in association with various experimental procedures.

Three different sieve size fractions of ergot-containing biodegradable microcapsules were examined both in vitro and in vivo. The sieve sizes and average particle diameter, (micron), were: less than 45-75 (mean = 30); 75-106 (mean = 79); 106-177 (mean = 130). These microcapsules contained ca. 9% drug and were produced from 50:50 poly(DL-lactide-co-glycolide). The objective was to determine the effect of particle size on in vivo and in vitro degradation rates. The microcapsules were injected into rat gastrocnemius muscle and excised and examined at various time points up to 70 days. Initially a minimal tissue response was noted which was characterized by a sharply localized acute inflammatory reaction. Following this, connective tissue and foreign body giant cells engulfed the microcapsules at 20-30 days. Only vestiges of the microcapsules were found surrounded by minimal connective tissue and foreign body giant cells after 60-70 days. The tissue reaction was a minimal, sharply localized foreign body giant cell and connective tissue process for all three size groups of microcapsules. The largest microcapsules (mean = 130 microns) exhibited a slightly greater tendency to undergo in vivo and in vitro degradation relative to the other groups. However, it can be concluded that over the microcapsule size ranges examined minimal differences in the degradation properties of the polymeric matrices and consequently those of the microcapsules were noted.

A computerized operator-interactive system for measurement of atheroma is described. The system utilizes a 64K microcomputer, a high resolution digitizer tablet, dual floppy disc drives, and a video monitor. The method offers significant advantages over earlier systems in speed, accuracy, reproducibility and cost effectiveness.

Adult male Sprague-Dawley rats maintained on a low sodium diet were administered 100 mg of cyclosporine per kg b.wt. per day s.c. for 4 to 10 days. Serum urea nitrogen was significantly elevated by day 4 and continued to rise, whereas serum creatinine was not elevated above control until day 10. Morphologic examination of perfusion-fixed kidneys from cyclosporine-treated rats revealed focal areas of tubular atrophy and interstitial fibrosis in the outer cortex and a generalized increase in interstitial cells in the outer medulla. No areas of acute tubular necrosis were identified. The effect of this dose of cyclosporine on renal hemodynamics was examined in conscious restrained rats. Renal blood flow, measured by microsphere injection, was 70% of control after four daily doses and remained near this level after eight daily doses. The glomerular filtration rate, measured by iodothalamate clearance, was 70% of control after four doses but fell to 34% of control after eight doses. [3H]Thymidine incorporation into renal DNA was used as a sensitive index of renal cell proliferation after cyclosporine administration (100 mg/kg/day). [3H]Thymidine incorporation was increased over control 3-fold in the outer cortex, 7-fold in the inner cortex and 11-fold in the medullary-papillary regions of the kidney after eight daily doses of cyclosporine. Histoautoradiographic examination of renal sections revealed an increase in the number of labeled nuclei in all three regions of the kidney from rats treated with cyclosporine. Morphometric analysis demonstrated that the majority of proliferating cells were located in the interstitium and not in renal tubules.(ABSTRACT TRUNCATED AT 250 WORDS)

Numerous amphiphilic cationic drugs cause generalized phospholipidosis in animals; one of these drugs is the Sandoz compound 200-125, a psychotropic agent. During a 6-month toxicity study in Charles River CD rats, a dramatic increase in foamy macrophages was seen in the lungs. A follow-up experiment was done to study the pathologic basis of these changes including a reversibility phase. Generalized phospholipidosis was induced after 4 weeks of 500 mg/kg/day of 200-125 by gavage. Characteristic pulmonary lesions consisted of extensive accumulations of large pale foamy macrophages as well as granular eosinophilic extracellular material. Lipid analyses of lungs showed marked increases in phospholipids (144%) and cholesterol esters (110%) in rats treated with 200-125. Drug metabolism studies employing 14C-labeled 200-125 showed an affinity for the drug to concentrate in the lungs and lymphoreticular system (spleen, lymph nodes) as well as in the adrenals, liver, and kidney. Reversibility of the phospholipidosis was nearly complete 4 weeks after drug withdrawal. The tissue changes were characterized by transmission and scanning electron microscopy. The potential pulmonary toxicity in humans with the amphiphiles is discussed.

Biodegradable microcapsules have been shown to be capable of delivering a sustained release of various medicinal agents. We have observed an initial minimal, sharply localized, acute inflammatory response to intramuscularly injected microcapsules produced from various polymers. Evaluation of later time points has shown a diminishing macrophage, foreign body giant cell, and connective tissue response along with actual microcapsule degradation. No fibrous capsule formation was seen. Complete resolution of the tissue reaction can be expected, with the time frame depending upon the polymer utilized. Published experimental results report similar minor tissue responses to a variety of injected biodegradable microcapsules.

The biodegradation of the copolymer 50:50 poly(DL-lactide-co-glycolide)-lypressin microcapsules was studied by light and electron microscopic methods and 14C release. Intramuscular injection sites of microcapsules in rats were studied by dissecting and conventional light microscopy as well as scanning (SEM) and transmission electron microscopy. A minimal localized acute myositis was seen initially at the injection sites. By Day 4, a few small foreign body giant cells were present participating in the minimal foreign body response. Later the inflammatory cells decreased and the individual microcapsules were walled off by immature fibrous connective tissue and large syncytial foreign body giant cells. By Day 35, definitive changes in some microcapsules, consisting of a granular and slightly eroded appearance of the internal matrix, were seen by SEM. By Day 42, the outer rims of the microcapsules were extensively eroded. At Day 56, the inflammatory and connective tissue reactions were almost completely resolved and biodegradation continued so that only remnant pieces of the microcapsules were present at Day 63. The morphologic picture correlated well with loss of 14C radioactivity, which could no longer be detected at the injection sites on Day 56. Phagocytosis did not seem to be an important factor in the biodegradation.